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LPA receptor agonists and antagonists and methods of use

Active Publication Date: 2006-01-12
UNIV OF TENNESSEE RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0046] Yet another aspect of the present invention relates to a method of enhancing cell proliferation which includes providing a compound the present invention which has activity as an agonist of an LPA receptor and contacting the LPA receptor on a cell with the compound in a manner effective to enhance LPA receptor-induced proliferation of the cell.
[0064] A further aspect of the present invention relates to a method of culturing cells which includes: culturing cells in a culture medium which includes a compound of the present invention which has activity as an agonist of an LPA receptor and is present in an amount which is effective to prevent apoptosis or preserve the cells in culture.
[0065] Another aspect of the present invention relates to a method of preserving an organ or tissue which includes: providing a compound of the present invention which has activity as an agonist of an LPA receptor; and treating an organ or tissue with a solution comprising the compound in an amount which is effective to preserve the organ or tissue function.

Problems solved by technology

However, these compounds have not been studied in all cell systems.

Method used

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  • LPA receptor agonists and antagonists and methods of use
  • LPA receptor agonists and antagonists and methods of use
  • LPA receptor agonists and antagonists and methods of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Phosphoric Acid di-tert-butyl Ester Alkenyl Esters (4a-f)

[0172] Commercially available unsaturated fatty alcohols (3a-f) were used as starting materials. To a stirred solution of alcohol (2.5 mmol) and di-tert-butyl-N,N-diisopropyl phosphoramidite (1.51 g, 4 mmol) in methylene chloride (60 mL) was added 1H-tetrazole (578 mg, 8.25 mmol). After 30 minutes of stirring the mixture was cooled to 0° C. and 0.3 mL of 50% hydrogen peroxide was added. The mixture was stirred for 1 h., diluted with methylene chloride (100 mL), washed with 10% sodium metabisulfite (2×50 ml), saturated sodium bicarbonate (2×50 ml), water (50 ml), and brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude products were purified by silica gel chromatography using hexane / ethyl acetate (7:3) to elute the desired products, di-t-Boc protected fatty alcohol phosphates (4a-f).

[0173] Phosphoric acid di-tert-butyl ester dec-9-e...

example 2

Synthesis of Phosphoric Acid Mono Alkenyl Esters (5a-f)

[0179] The Boc-protected FAPs (4a-f) were deprotected with TFA to yield the corresponding unsaturated FAPs (5a-f). To a solution of 100 mg of 1a-6a in methylene chloride (20 mL), trifluroacetic acid (0.3 mL) was added. The mixture was allowed to stir for 4 h., and TLC showed the completion of the reaction. Solvents were evaporated; the residue was washed with methylene chloride (2×20 mL), and concentrated under vacuum to yield the desired phosphoric acid mono alkenyl esters as colorless oils.

[0180] Phosphoric acid monodec-9-enyl ester (5a): Isolated as an oil (85%). 1H NMR (MeOH-d4): δ 5.74 (m, 1H), 4.88 (m, 2H), 3.90 (q, J=6.6 Hz, 2H), 2.01 (q, J=6.9 Hz, 2H), 1.61 (quintet, 2H), 1.28 (br s, 10H); 31PNMR (MeOH-d4): δ 17.84; MS: [M−H]− at m / z 235.2. Anal. (C10H21O4P.0.1H2O)C, H.

[0181] Phosphoric acid monodec-4-enyl ester (5b): Isolated as an oil (78%). 1H NMR (MeOH-d4): δ 5.31 (m, 2H), 3.84 (q, J=6.8 Hz, 2H), 2.05 (q, J=7.0 Hz...

example 3

Synthesis of Thiophosphoric Acid O,O′-bis-(2-cyano-ethyl) Ester O″-alkyl / alkenyl Esters (7a-g)

[0186] Commercially available saturated or unsaturated fatty alcohols (6a-g) were used as starting materials. A solution of alcohol (2.0 mmol), bis-(2-cyanoethyl)-N,N-diisopropyl phosphoramidite (1.085 g, 4 mmol) and 1H-tetrazole (420 mg, 6 mmol) was stirred for 30 minutes at room temperature, followed by the addition of elemental sulfur (200 mg) and the mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature and solvents were evaporated under vacuum. Addition of ethyl acetate (30 mL) precipitated excess sulfur, which was filtered out, and the solvent was evaporated to give the crude mixture. The mixture was purified by flash chromatography to give the desired products as colorless oils.

[0187] Thiophosphoric acid O,O′-bis-(2-cyano-ethyl) ester O″-decyl ester (7a): Isolated as colorless oil (72% yield). 1H NMR (CDCl3): δ 4.21-4.35 (m, 4H), 4.12 (m, 2H), 2.8 (t, J=...

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Abstract

The present invention relates to compounds according to formula (I) as disclosed herein as well as pharmaceutical compositions which include those compounds. Also disclosed are methods of using such compounds, which have activity as agonists or as antagonists of LPA receptors; such methods including inhibiting LPA activity on an LPA receptor, modulating LPA receptor activity, treating cancer, enhancing cell proliferation, treating a wound, treating apoptosis or preserving or restoring function in a cell, tissue, or organ, culturing cells, preserving organ or tissue function, and treating a dermatological condition.

Description

[0001] This application claims the priority benefit of U.S. Provisional Patent Application Ser. No. 60 / 509,971, filed Oct. 9, 2003, which is hereby incorporated by reference in its entirety.[0002] This invention was funded, in part, by the National Institutes of Health Grant No. CA92160. The U.S. government may have certain rights in this invention.FIELD OF THE INVENTION [0003] This invention relates to lysophosphatidic acid (“LPA”) derivatives which have activity as either agonists or antagonists on LPA receptors and various therapeutic uses thereof including, but not limited to, prostate cancer therapy, ovarian cancer therapy, and wound healing. BACKGROUND OF THE INVENTION [0004] All non-transformed cells require growth factors for their survival and proliferation. In addition to polypeptide growth factors, an emerging class of lipids with growth factor-like properties has been discovered, collectively known as phospholipid growth factors (PLGFs). In spite of their similar pharmac...

Claims

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Application Information

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IPC IPC(8): A61K31/40C07D207/02A61KC03C27/02C07F9/11C07F9/113C07F9/165C07F9/17C07F9/173C07F9/38C07F9/40
CPCA61K31/661A61K31/675C07F9/11C07F9/113C07F9/4006C07F9/1653C07F9/17C07F9/173C07F9/3808C07F9/1651A61P1/04A61P1/12A61P17/00A61P17/02A61P35/00A61P43/00C07F9/30C07C233/05A61K31/662
Inventor MILLER, DUANE D.TIGYI, GABORDURGAM, GANGADHAR G.VIRAG, TAMASWALKER, MICHELLE D.TSUKAHARA, RYOKO
Owner UNIV OF TENNESSEE RES FOUND
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